The ALL-HAT trial is by far the most important clinical trial ever done in the management of hypertension. It answers the question: Which class of antihypertensive medication is the best for reducing cardiovascular disease? And it is the definitive source for the answer. They randomised a whopping 42,000 patients to get one of the four antihypertensive medications: an ACE-inihibitor, a calcium channel blocker, a thiazide or an alpha-blocker. The ACE-inihibitor they used was lisinopril, the calcium channel blocker was amlodipine, the thiazide was chlorthalidone and the alpha-blocker was doxazocin. They followed for between 4-8 years and they where interested in how many in each group develop cardiovascular disease. Perhaps one class of antihypertensive is better than the others?

The trial was started in the mid-90s, when the thiazide, chlorthalidone, had been around for ages and the case for lowering blood pressure was now well established. Lot’s of new agents were coming to market and each being vastly more expensive chlorthalidone. So the authors were interested in whether the more expensive drugs at the time: ACI inhibitors, Calcium channel blockers or alpha blockers were actually any better than good old cheap chlorthalidone?

Methods

The 42,000 participants were recruited from 623 centres in the US, Canada and Puerto Rico between 1994 and 1998. There were three main inclusion criteria:

They had to be 55 years old or older

They had to have hypertension as defined as either a systolic BP greater than 140 or a diastolic BP greater than 90.

They had to have one additional risk factor for cardiovascular disease on top of hypertension. And this could be: Either a previous heart attack, type 2 diabetes, currently smoking, left ventricular hypertrophy on ECG or echo or an elevated cholesterol.

The only excluded those who had symptomatic heart failure. They did not exclude patients who were already taking antihypertensive, in fact, 90% of them were, but they stopped them all when the study started. On the day of randomisation, they stopped all of their antihypertensives, then the next day they started their study drug. That way they were testing that particular drug in the purest way possible.

They concealed allocation and randomised to a 1.7:1:1:1 ratio so that more participants were in the thiazide group. Around 15,000 were randomised to chlorthalidone and around 9000 to each of doxazocin, lisinopril and amlodipine. They stopped the trial in 2002 so those who were recruited in 1994 were followed up for 8 years while those were recruited in 1998 were followed up for 4 years. On average, the follow up was 5 years. They followed them up every 3 months in the first year then every 4 months in the following years. They would increase the dose of the study drug to get the BP to a target of below 140/90. If they couldn’t do that with maximal dose, then they would add in either atenolol, clonidine or reserpine and this was up to the doctor.

Alpha-Blocker (Doxazocin)

They stopped the doxazosin (Cardura) arm of the trial early because an interim analysis showed that it was inferior. They published this interim analysis on doxazosin in a separate article before the results of the main trial came out. It was in JAMA in the year 2000. After an average of 3.3 years of follow up for this interim analysis, they found that compared to the thiazide chlorthalidone:

Those getting doxazocin had a 25% increase in adverse cardiovascular outcomes – it went from 21.67% in the chlorthalidone group to 25.45% in the doxazocin (NNH 27). Which means that for every 27 patients you decide to treat with doxazocin over chlorthalidone, 1 will develop a cardiovascular event.

Congestive heart failure doubled. It went from 4.45% in the chlorthalidone group to 8.13% in the doxazosin group making a number needed to harm of 27.

Now, this was the first ever decent study to compare an alpha blocker to another class of antihypertensive and while it should have spelt the end of doxazosin for the treatment of hypertension…it didn’t! Pfizer, who brought doxazosin to market under the brand name “Cardura”, was also one of the sponsors of the ALLHAT trial. So they became aware of these results before the trial was published. So what do you do when one of your drugs is found to be harming people? Do you pull it from the market? Or perhaps you put a little warning on the box? No. You create a marketing and damage control campaign. In fact, the sales of Doxazosin or Cardura where completely unscathed after this trial was published with virtually no change in the $800 million dollars of sales per year for this drug.

Some internal documents leaked from Pfizer to show the techniques they used. They got an external research agency to study the doctors’ awareness of this preliminary report from the ALLHAT trial. When the agency found that “knowledge of the trial’s preliminary results is minimal for all specialities,” they took great steps to make sure, as best as possible, that word did not get out. Firstly, Pfizer deliberately did not issue a statement about the ALLHAT results, because it “would likely draw more media attention to the situation.” Secondly, they taught their drug reps to provide information about the ALLHAT trial “only when asked.” And how’s this for a bit of genius: At the American College of Cardiology conference in California in the year 2000, Dr. Furberg, who is the lead researcher of the ALLHAT trial, was set to give a presentation on the ALLHAT results. So what did Pfizer do? They brought in the top big shots in cardiology to do a tour at the same time as the presentation. Therefore keeping doctors who attended the conference from attending the talk on the ALLHAT trial. In fact, a document leaked where the two Pfizer employees who came up with this idea were praised as being “quite brilliant” by their management.

The blood pressure reductions between chlorthalidone and doxazosin were pretty much the same – Around 2mmHg between them. So I think this is an important lesson that blood pressure reduction is not equal. A 10mmHg reduction in blood pressure with one class of drug will impact on cardiovascular disease differently than a 10mmHg reduction with another drug. And this is the same for everything: cholesterol, HBA1c, and it’s why we need to ask for clinical trials to show us the impact on hard outcomes rather than these surrogate markers.

Calcium Channel Blockers (Amlodipine)

The primary outcome, which was fatal or non-fatal heart attacks was the same in all three groups. It occurred in 11.5% of the participants regardless of which antihypertensive they got.

But, it’s in the secondary outcomes where some differences lie. And seem to be in favour of chlorthalidone:

There was a 40% relative increase in heart failure with amlodipine compared to chlorthalidone it went from 7.7% to 10.2% (NNH 40).

There was an increase in coronary revascularization with amlodipine as well, it went from 9.2% to 10%, (the P-value was 0.06 though).

Peripheral vascular disease decreased by 0.4% with amlodipine – from 4.1% to 3.7% (again the P-value was 0.6 – just short of that arbitrary cut off for statistical significance).

All the other outcomes: stroke, end-stage renal disease, cancer and all-cause mortality were the same between the two. And it didn’t matter if they were male or female, older or younger, black or white or diabetic or non-diabetic, the results were consistent across all those groups.

ACE Inhibitor – Lisinopril

Here again, chlorthalidone came out on top.

There was a 15% relative increase in stroke with the ACE inhibitor compared to the thiazide: It went from 5.6% to 6.3% (NNH of 143).

The combined cardiovascular outcome was also worse for the ACE inhibitor – it went from 30.9% to 33.3%, (NNH 41).

Heart failure was also worse with lisinopril (NNH 100).

More people developed angina with lisinopril, (NNH 67), and more coronary revascularization.

End-stage renal failure was not different between the groups – it was 2% for those taking lisinopril versus 1.8% in those taking chlorthalidone.

There was also no difference in all-cause mortality, peripheral arterial disease or cancer.

They did a lot of subgroup analyses and did show that within certain age ranges and within certain races, lisinopril was not worse than chlorthalidone:

Age: When they looked at those under the age of 65 there was no difference in the combined cardiovascular disease outcome between lisinopril and chlorthalidone. It was only in those over the age of 65, where lisinopril was worse.

Race – lisinopril was worse in black people. There was a 40% increase in stroke in black people taking lisinopril, but no increase in stroke rates in white people taking lisinopril. Similarly, with the combined cardiovascular outcome, it increased by 20% in black people taking lisinopril but only increased by 6% in white people taking lisinopril.

Diabetics status: The outcomes were consistent with the overall findings

Gender: The outcomes were consistent with the overall findings

Blood Pressure Targets

The blood pressure achieved in each of the three groups were actually statistically difference. Whether they were clinically or meaningfully different is another story. So at 5 years, the systolic BP was 134 for chlorthalidone, 134.7 for amlodipine and 135.9 for lisinopril. So a 2mmHg difference between chlorthalidone and lisinopril. Could that be the sole reason for the worse outcomes with lisinopril? I highly doubt it but could be. And even if it is, it still puts thiazides ahead in my books because great…it’s better at reducing blood pressure than the others.

Side Effects

At the end of 5 years, 20% of those in each of the chlorthalidone and the amlodipine group were no longer actually taking those drugs. While 27% were no longer taking lisinopril by this time. The most common reason was that of adverse effects or the patient refused to take it after a certain point. So it seems more people were stopping the lisinopril. They did collect some limited data on other adverse events. Angioedema occurred 4 times more in the lisinopril group than the other groups but it was still pretty rare occurring in about 1 in every 250 people taking lisinopril. They measured potassium levels and found that hypokalaemia occurred more commonly with chlorthalidone. At the start of the study, before any of them were given their study drug, around 3% had a potassium less than 3.5. In those randomised to chlorthalidone, 8.5% developed a potassium less than 3.5, while only 1% did with lisinopril and 1.9% with amlodipine.

Statin Arm Of the Trial

For everyone who had elevated cholesterol in this study, of which there were 20,000, they randomised them to either get a statin or a placebo. I guess they thought: “well, we’re spending billions of dollars recruiting and following these people up, we might as well check if statins work as well”. This arm of the study will not be discussed here,

Bottom Line:

The ALLHAT study is the most definitive study to compare different classes of antihypertensives in terms of their ability to reduce cardiovascular disease. They found that the alpha-blocker – doxazocin (Cardura) was significantly inferior, causing double the rate of congestive cardiac failure and a 25% relative increase in cardiovascular disease compared to chlorthalidone. The calcium channel blocker, Amlodipine was equivalent to chlorthalidone in terms of heart attacks, strokes and cardiovascular disease, but in terms of heart failure, Chlorthalidone was superior – treatment with amlodipine resulted in a 40% increase in congestive cardiac failure (NNH 40). Chlorhalidone seemed to be superior to the ACE-inhibitor lisinopril as well – treatment with lisinopril resulted in a 15% relative increase in stroke compared to treatment with chlorthalidone. It also resulted in an increase in cardiovascular disease (NNH 41) and heart failure (NNH 100). This increase in adverse cardiovascular outcomes with ACE-inhibitors where much less profound in a subgroup analysis of only white people.

Guidelines

So how did the guidelines respond to this piece of evidence?

American guidelines (JNC 8):

“In the general nonblack population, including those with diabetes, initial anti-hypertensive treatment should include a thiazide diuretic, calcium channel blocker, angiotensin-converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB). In the general black population, including those with diabetes, initial treatment should include a thiazide diuretic or calcium channel blocker.

Australian Heart Foundation Hypertension guidelines:

“In patients with uncomplicated hypertension ACE inhibitors or ARBs, calcium channel blockers, and thiazide diuretics are all suitable first-line antihypertensive drugs, either as monotherapy or in some combinations unless contraindicated”.

UK NICE guidelines

For under 55 they recommend starting with an ACE or an ARB. For over 55 or for black people they recommend starting with a calcium channel blocker. If a calcium channel blocker is not tolerated then a thiazide diuretic. For under 55 they recommend starting with an ACE or an ARB. For over 55 or for black people they recommend starting with a calcium channel blocker, if a calcium channel blocker is not tolerated then a thiazide diuretic. They actually recommend using chlorthalidone or indapamide as the thiazide of choice rather than hydrochlorothiazide. NICE also recommend to: ” Prescribe non-proprietary drugs where these are appropriate and minimise cost”

And while we’re on the topic of cost, here is a quote from the conclusion of the ALLHAT trial article:

“One of the stated objectives of ALLHAT was to answer the question, “Are newer types of antihypertensive agents, which are currently more costly, as good or better than diuretics in reducing CHD incidence and progression?”18 Consideration of drug cost could have a major impact on the nation’s health care expenditures. Based on previous data that showed that diuretic use declined from 56% to 27% of antihypertensive prescriptions between 1982 and 1992, the health care system would have saved $3.1 billion in estimated cost of antihypertensive drugs had the pattern of prescriptions for treatment of hypertension remained at the 1982 level”